Treatment of Recurrent ALL
Treatment of Extramedullary Relapse
With the improved success of treatment of children with ALL, the incidence of isolated extramedullary relapse has decreased. The incidence of isolated CNS relapse is less than 5% and testicular relapse is less than 1% to 2%.[65,66,67] Age older than 6 years at diagnosis is an adverse prognostic factor for patients with an isolated extramedullary relapse. In the majority of children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques, and successful treatment strategies must effectively control both local and systemic disease. Patients with an isolated CNS relapse who show greater than 0.01% MRD in a morphologically normal marrow have a worse prognosis compared with patients with either no MRD or MRD less than 0.01%.
While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy followed by cranial or craniospinal radiation has improved the outlook, particularly for patients who did not receive cranial radiation during their first remission.[15,70,71,72] In a Pediatric Oncology Group (POG) study using this strategy, children who had not previously received radiation therapy and whose initial remission was 18 months or greater had a 4-year EFS rate of approximately 80% compared with EFS rates of approximately 45% for children with CNS relapse within 18 months of diagnosis. In a follow-up POG study, children who had not previously received radiation therapy and with initial remission of 18 months or more were treated with intensive systemic and intrathecal chemotherapy for 1 year followed by 18 Gy of cranial radiation only. The 4-year EFS was 78%. Children with an initial remission of less than 18 months also received the same chemotherapy but had craniospinal radiation (24 Gy cranial/15 Gy spinal) as in the first POG study and achieved a 4-year EFS of 52%.
A number of case series describing SCT in the treatment of isolated CNS relapse have been published.[73,74] In a study comparing outcome of patients treated with either HLA-matched sibling transplants or chemoradiotherapy as in the POG studies above, 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar (58% and 66%, respectively).[Level of evidence: 3iiiDii] This retrospective, registry-based study included transplantation of both early (<18 months from diagnosis) and late relapses. Because of the relatively good outcome of patients with isolated CNS relapse more than 18 months from diagnosis treated with chemoradiation therapy alone (>75%), transplantation is generally not recommended for this group. However, use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study. The use of post-HSCT intrathecal chemotherapy has been controversial, although the most current data would suggest no benefit.